How TMAO Fooled Us

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
BrianR
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How TMAO Fooled Us

Post by BrianR »

https://lesslikely.com/nutrition/tmao-m ... omization/ analyzes a new paper (see below) which suggests "... that T2DM and kidney disease increase TMAO levels and observational evidence for cardiovascular diseases may be due to confounding or reverse causality."

The analysis seems plausible-ish, although I'm not really qualified to assess it rigorously. I like the idea advanced by the analysis, because it's convenient for me, but I guess we'll see how the science holds up over time.

The paywalled paper is:

Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: Abi-Directional Mendelian Randomisation Analysis
https://diabetes.diabetesjournals.org/c ... /db19-0153
Jinzhu Jia, Pan Dou, Meng Gao, Xuejun Kong, Changwei Li, Zhonghua Liu, Tao Huang
Diabetes 2019 Jun; db190153.
DOI 10.2337/db19-0153

Abstract
We examined the causal direction between gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) or its predecessors and cardiometabolic diseases such as risk of type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), myocardial infarction (MI), stroke, atrial fibrillation (AF), and chronic kidney disease (CKD). We used genetic variants as instruments to test the causal associations. Genetically predicted higher TMAO and carnitine were not associated with higher odds of T2DM, AF, CAD, MI, stroke, and CKD after Bonferroni correction (P≤0.0005). However, we observed that genetically increased choline showed a suggestive association with higher risk of T2DM (odds ratio: 1.84, 95% confidence interval: 1.00 to 3.42 per 10 units, P=0.05). In contrast, genetically predicted higher betaine (0.68, 0.48 to 0.95 per 10 units, P=0.023) was suggestively associated with a lower risk of T2DM. We observed a suggestive association of genetically increased choline with a lower level of body fat % (beta: -0.28, SE: 0.11, P=0.013), but a higher level of estimated glomerular filtration rate (0.10±0.05, P=0.034). We further found that T2DM (beta: 0.130, SE: 0. 0.036, P<0.0001) and CKD (0.483±0.168, P=0.004) were causally associated with higher TMAO levels. Our MR findings support that T2DM and kidney disease increase TMAO levels and observational evidence for cardiovascular diseases may be due to confounding or reverse causality.
(I didn't read this paper, but some may be motivated to dive into it.)
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Julie G
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Re: How TMAO Fooled Us

Post by Julie G »

Really interesting, Brian. Because TMAO is created in the gut, I always thought that overall gut health would also play a significant role.
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SusanJ
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Re: How TMAO Fooled Us

Post by SusanJ »

Back to TMAO and whether to be worried or not.

Here is a new review from Sarah Ballantyne about TMAO, prompted by a new study (full text) that looked at Paleo eaters and TMAO. Bottom line is that she is encouraging Paleo and low-fat folks to eat a diet with a more moderate carbohydrate intake - 30 to 60% of total calories, from whole food sources.

Very much worth the time to read through this, and feel free to draw your own conclusions as to what will work for you.

https://www.thepaleomom.com/paleo-resis ... h-heeding/
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Re: How TMAO Fooled Us

Post by zc_hl »

This one is also interesting:
Is increased plasma TMAO a compensatory response to hydrostatic and osmotic stress in cardiovascular diseases? (https://www.ncbi.nlm.nih.gov/m/pubmed/31383335/)

TMAO is an osmolyte which protects against osmotic stress.
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Re: How TMAO Fooled Us

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I find the articles on TMAO feeding to promote cardiovascular disease somewhat convincing.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300890/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943035/

It doesn't seem so much like an unhealthy diet or kidney disease happens to be associated with this TMAO marker, and that TMAO marker is associated with CVD. But, it does feel a bit like TMAO itself is a bit of an additive driver. (I'd love to see more research to show this isn't the case.)

A 30-60% CHO macro seems like it would still produce plenty of TMAO if you're eating choline / carnitine. Although, a high-fat diet low in choline / carnitine seems like a bad idea. Tricky.
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Re: How TMAO Fooled Us

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It seems to me that intermittent fasting blunts the negative effects of so many things, so I wondered if it would blunt overall TMAO response the way it can mTOR and IGF1. This recent paper begins to explore the notion and finds that with 24 hour water fasting TMAO levels drop before rebounding on refeeding. Was that a surprise?

https://www.ncbi.nlm.nih.gov/pmc/articl ... n_sectitle

Of course high fat and low animal would still lower overall levels, but where’s the health vs disease cutoff and how is it modified by individual physio-biomic-genetic-ology?

My vote with “high” animal feeding (not beyond leucine needs) is to follow Gabriel Lyon’s three protein meals a day with four hours in between to reset mTOR plus long fast at night (but wouldn’t be as long as some here do). This would keep the area under the curve lower?

That’s assuming TMAO is bad for a particular individual. My coronary calcium scan is 0. Do I get a pass? Does the scan trump TMAO levels as long as its results don’t change?
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: How TMAO Fooled Us

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apod wrote:I find the articles on TMAO feeding to promote cardiovascular disease somewhat convincing.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300890/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943035/

It doesn't seem so much like an unhealthy diet or kidney disease happens to be associated with this TMAO marker, and that TMAO marker is associated with CVD. But, it does feel a bit like TMAO itself is a bit of an additive driver. (I'd love to see more research to show this isn't the case.)

A 30-60% CHO macro seems like it would still produce plenty of TMAO if you're eating choline / carnitine. Although, a high-fat diet low in choline / carnitine seems like a bad idea. Tricky.
apod see my comment just above too (forgot to quote.).

The first article you link is interesting by linking TMAO to reduced and deranged bile acid synthesis. I’ve fallen off on my use of Flora’s alcohol free bitters in recent months, but now I’ll use them again when I eat meat, plus of course adding the bitter foods. Bitter is supposed to stimulate bile, and a huge problem with the modern industrial diet is a relative lack of bitter foods relative to our ancestors. I wonder if the proverbial ‘early man’ that ate high amounts of animal was compensating for TMAO by ingesting a lot of bitter plant foods that melt the bile flowing.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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SusanJ
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Re: How TMAO Fooled Us

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apod wrote:A 30-60% CHO macro seems like it would still produce plenty of TMAO if you're eating choline / carnitine. Although, a high-fat diet low in choline / carnitine seems like a bad idea. Tricky.
Ballantyne points out a paradox that fish is very high in TMAO, but is found to be generally heart healthy. And some folks eat fish and their circulating TMAO is low; for others it's high. So, Ballantyne argues that the increase of good carbs helps sustain a better mix of microbes that either don't produce it in the first place (e.g. increasing Bifidos while likely decreasing Prevotella) or help break down TMAO (e.g. Archaea). See Archaea-related quote at the bottom.

circular wrote:Bitter is supposed to stimulate bile, and a huge problem with the modern industrial diet is a relative lack of bitter foods relative to our ancestors. I wonder if the proverbial ‘early man’ that ate high amounts of animal was compensating for TMAO by ingesting a lot of bitter plant foods that melt the bile flowing.
Bile is an interesting connection here, since it is very connected to microbiota.

Bile Acids and the Gut Microbiome

And Ben Lynch is a proponent of using ox bile and herbal antibiotics for SIBO, because both will help kill off bugs in the SI that shouldn't be there.

So, looks like to me, that bile is also an important part of keeping the right balance of microbiota in the gut.


Archaea: A Microbiome Missing Piece

Archaea degrade TMA and TMAO
One important subtype of archaea are the methanogens, which produce methane gas as a byproduct of hydrogen reduction. Up to 95% of human guts harbor the methanogenic archaea Methanobrevibacter smithii and Methanosphaera stadtmanae, at varying levels. While the idea of producing methane might not sound very pleasant, some of these archaea (in particular, an order of methanogens called the Methanomassiliicoccales) actually play an integral role in reducing our TMAO production. Along with being able to use carbon dioxide, formate, and methanol (all released by bacteria breaking down food and other organic matter in the gut), these archaea can use methyl compounds like TMA and TMAO to generate methane. And that means that the archaea in our gut actually deplete the pool of TMA we have available to be converted into TMAO (along with any free TMAO from foods like seafood). So, all that TMA generated by Prevotella, or entering our body from fish consumption? Archaea can help wipe some of it out!

The TMAO-reducing effects of archaea is far from just speculative, too. In a study of ELDERMET subjects, the fecal TMA concentration in people with TMA-metabolizing archaea was significantly lower than in those without this archaea—and the difference was particularly dramatic when the abundance of Methanomassiliicoccales was greater than 10^8 cells per gram of stool. This role of archaea is so exciting that some scientists are proposing a new class of probiotics called archaeabiotics, which could help reduce our TMAO levels without us needing to cut back on choline and other important nutrients!

Importantly, methanogenic archaea have an important interactive relationship with bacteria in the gut, which often takes the form of what scientists call syntrophy (where two organisms participate in consuming a substance that neither one can catabolize on its own). And, it appears that archaea are particularly chummy with the important probiotic bacteria Bifidobacteria. For example, mixed cultures of M. smithii and Bifidobacteria bifidum have been shown to collectively produce methane from glucose, and in females with gut Methanobacteriales levels higher than 0.71%, there’s a significantly higher mean abundance of Bifidobacteriaceae. And as we’ve already seen, healthy levels of Bifidobacteria are super important!

Archaea Thrive When We Eat Carbs!
So, how do we keep our archaea happy and thriving? Scientists are just at the beginning stages of understanding how diet impacts our archaea colonies (after all, archaea are relative newcomers to the microbiota research scene compared to bacteria!), but here’s what we know so far. In children, organic dairy (especially organic yogurt and organic milk) has been associated with the initial colonization of M. smithii, due to organic dairy serving as a vehicle for delivering it to our guts. And, some methanogens degrade methanol, which gets produced when bacteria degrade pectin in fruits—thus suggesting that archaea might benefit from including fruit in our diets! In Chinese goats, eating a high-grain diet appears to suppress methanogenic archaea relative to a high-hay diet—possibly due to the pH-lowering effect of grains in the rumen (which can then suppress methanogenic archaea that are sensitive to low pH environments). Obviously, we’re not Chinese goats, but it would certainly be interesting if a high-grain diet in humans had a similar effect!

More broadly, though, in humans, Methanobrevibacter abundance is positively associated with higher carbohydrate consumption (both recent and long-term), and negatively associated with recent consumption of fat (especially vegetable fat and polyunsaturated fat intake) and amino acids. Although more research is definitely needed, the picture getting painted so far is that archaea benefit from a variety of plant polysaccharides, and not so much from animal-based diets.

However, this isn’t because the archaea themselves eat carbohydrate. In fact, methanogenic archaea have an almost complete lack of enzymes for breaking down complex carbohydrates into simple sugars. What does appear to be happening is that archaea thrive off the metabolic products of carbohydrate-loving bacteria, and therefore are still dependent on dietary carbohydrate for their own survival!
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Julie G
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Re: How TMAO Fooled Us

Post by Julie G »

I just have a moment for a quick drive-by, but I encourage anyone who wants the low down on TMAO to read Susan's link to Sarah Ballantyne's article. It's very thoughtful; the best summary I've encountered so far. I'm also interested in the bile link. It makes so much sense given that TMAO is created in the gut and we need bile to properly break down our foods. I like bitters and ox bile, but given that proteins are the main drivers of TMAO I suspect that betaine (with pepsin) might be even more helpful as that's what specifically breaks down protein.
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Re: How TMAO Fooled Us

Post by circular »

Julie G wrote:I like bitters and ox bile, but given that proteins are the main drivers of TMAO I suspect that betaine (with pepsin) might be even more helpful as that's what specifically breaks down protein.
What are we coming to when we casually comment "I like ox bile"? :lol:

For the betaine, I take it in the morning. Do you think that would help me digest protein all day, or does one need to take it with the protein? (If you know or have a thought.)
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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